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A closer look at molecular risk factors for diabetic kidney disease and effect on life span and heart disease

A closer look at molecular risk factors for diabetic kidney disease and effect on life span and heart disease

News / 23 August 2016

We are well versed on the links between diet, diabetes, obesity, and heart disease. Yet the conversation around diabetic kidney disease, and the effect on heart disease and lifespan, remains largely unspoken.

One in ten Australia adults exhibit biomedical signs of kidney disease, with chronic diabetics and indigenous Australians highly susceptible. A/Prof Ville-Petteri Mäkinen's research group at the EMBL Australia SA node (SAHRMI) is investigating the molecular risk factors for diabetic kidney disease, and its effects on heart disease and life span in Type I diabetics.

Finland, Mäkinen’s home country, has the highest incidence of Type I diabetes world-wide, which presents major clinical challenges when looking at the substantial risk for kidney disease, and the associated clinical challenges. It is this shocking statistic that triggered his interest in this research area.

Mäkinen entered the world stage of diabetic research almost ten years ago, when in 2008 he published a paper in Diabetes on the biochemical “subtypes” of Type I diabetics, and their risk of premature death. This important research provides the potential for precision prescription of treatment, where different subtypes are targeted in a unique manner. Fast forward seven years, and Mäkinen and his research group are collaborating with Finnish researcher Dr Raija Lithovius, where they have re-examined the subtypes with newly available data on mortality, heart and kidney disease, and cumulative medication costs.

“The study is a unique opportunity to test the original subtype models from 2008” explains Mäkinen, and “one of the first true examples of validated subtyping in the field of diabetic complications”. Mäkinen and his colleagues also applied advanced mathematical techniques, making it possible to integrate the population-level registry data from Finland with the specific age and observation patterns in the Finn-Diane cohort.

The results from the analysis were both expected and surprising. The five original subtypes identified in the original cohort were replicated, with no difference in standardised all-cause mortality between the first period of 1997-2007, and the second period of 2008-2015 in any of the subtypes. However, the research team uncovered a disappointing realisation. The relative risk of premature death due to Type I diabetes had not changed within the last decade, despite continuing advances in treatments.

The research also uncovered a striking gender difference. Here, females with an advanced kidney disease Type I diabetes subtype displayed a 46-fold greater risk of cardiovascular disease compared to their peers in the general population. This finding highlights the need to identify the specific molecular trigger in this subtype, to help improve mortality outcomes.

Luckily, there is hope in the horizon. Metabolically favourable subtypes had only modest increases in cardiovascular risk, with similar mortality rates as their peers in the general population. This finding suggests that strategies which result in observable normalisation of systemic metabolism are appearing to be very effective.

The next step in the research teams journey will focus on new ways to track, and ultimately prevent kidney disease, including the early detection of vulnerable subgroups in the population. They are looking to harness the large volume of data they have at their disposal, by investigating metabolomics and the genetic determinants of metabolic measures to identify pathways, and key driver genes, providing promising candidates for further mechanistic studies.

Later this month, Professor Mäkinen and Dr Stefan Mutter (Post-doc Research Fellow at EMBL) will present new data from the Finnish Diabetic Nephropathy Study in the annual meeting of the Australian Diabetes Society on the Gold Coast in Queensland.